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Title: Synchrotron Infrared Microspectroscopy Detecting the Evolution of Huntingtons Disease Neuropathology and Suggesting Unique Correlates of Dysfunction in White versus Gray Brain Matter

Abstract

Huntington's disease (HD), caused by a mutation of the corresponding gene encoding the protein huntingtin (htt), is characterized by progressive deterioration of cognitive and motor functions, paralleled by extensive loss of striatal neurons. At the cellular level, pathogenesis involves an early and prolonged period of neuronal dysfunction followed by neuronal death. Understanding the molecular events driving these deleterious processes is critical to the successful development of therapies to slow down or halt the progression of the disease. Here, we examined biochemical processes in a HD ex vivo rat model, as well as in a HD model for cultured neurons using synchrotron-assisted Fourier transform infrared microspectroscopy (S-FTIRM). The model, based on lentiviral-mediated delivery of a fragment of the HD gene, expresses a mutant htt fragment in one brain hemisphere and a wild-type htt fragment in the control hemisphere. S-FTIRM allowed for high spatial resolution and distinction between spectral features occurring in gray and white matter. We measured a higher content of {beta}-sheet protein in the striatal gray matter exposed to mutant htt as early as 4 weeks following the initiation of mutant htt exposure. In contrast, white matter tracts did not exhibit any changes in protein structure but surprisingly showed reducedmore » content of unsaturated lipids and a significant increase in spectral features associated with phosphorylation. The former is reminiscent of changes consistent with a myelination deficiency, while the latter is characteristic of early pro-apoptotic events. These findings point to the utility of the label-free FTIRM method to follow mutant htt's {beta}-sheet-rich transformation in striatal neurons ex vivo, provide further evidence for mutant htt amyloidogenesis in vivo, and demonstrate novel chemical features indicative of white matter changes in HD. Parallel studies in cultured neurons expressing the same htt fragments showed similar changes.« less

Authors:
; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE SC OFFICE OF SCIENCE (SC)
OSTI Identifier:
1041612
Report Number(s):
BNL-96841-2012-JA
Journal ID: ISSN 0003-2700; R&D Project: LS001; TRN: US201212%%30
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Journal Name:
Analytical Chemistry
Additional Journal Information:
Journal Volume: 83; Journal Issue: 20; Journal ID: ISSN 0003-2700
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; BRAIN; DISEASES; GENES; IN VIVO; LIPIDS; MOTORS; MUTANTS; MUTATIONS; NERVE CELLS; PATHOGENESIS; PHOSPHORYLATION; PROTEIN STRUCTURE; PROTEINS; SPATIAL RESOLUTION; SYNCHROTRONS; TRANSFORMATIONS

Citation Formats

Bonda, M, Miller, L, Perrin, V, Vileno, B, Runne, H, Kretlow, A, Forro, L, and and Jeney S, Luthi-Carter R. Synchrotron Infrared Microspectroscopy Detecting the Evolution of Huntingtons Disease Neuropathology and Suggesting Unique Correlates of Dysfunction in White versus Gray Brain Matter. United States: N. p., 2011. Web. doi:10.1021/ac201102p.
Bonda, M, Miller, L, Perrin, V, Vileno, B, Runne, H, Kretlow, A, Forro, L, & and Jeney S, Luthi-Carter R. Synchrotron Infrared Microspectroscopy Detecting the Evolution of Huntingtons Disease Neuropathology and Suggesting Unique Correlates of Dysfunction in White versus Gray Brain Matter. United States. doi:10.1021/ac201102p.
Bonda, M, Miller, L, Perrin, V, Vileno, B, Runne, H, Kretlow, A, Forro, L, and and Jeney S, Luthi-Carter R. Fri . "Synchrotron Infrared Microspectroscopy Detecting the Evolution of Huntingtons Disease Neuropathology and Suggesting Unique Correlates of Dysfunction in White versus Gray Brain Matter". United States. doi:10.1021/ac201102p.
@article{osti_1041612,
title = {Synchrotron Infrared Microspectroscopy Detecting the Evolution of Huntingtons Disease Neuropathology and Suggesting Unique Correlates of Dysfunction in White versus Gray Brain Matter},
author = {Bonda, M and Miller, L and Perrin, V and Vileno, B and Runne, H and Kretlow, A and Forro, L and and Jeney S, Luthi-Carter R},
abstractNote = {Huntington's disease (HD), caused by a mutation of the corresponding gene encoding the protein huntingtin (htt), is characterized by progressive deterioration of cognitive and motor functions, paralleled by extensive loss of striatal neurons. At the cellular level, pathogenesis involves an early and prolonged period of neuronal dysfunction followed by neuronal death. Understanding the molecular events driving these deleterious processes is critical to the successful development of therapies to slow down or halt the progression of the disease. Here, we examined biochemical processes in a HD ex vivo rat model, as well as in a HD model for cultured neurons using synchrotron-assisted Fourier transform infrared microspectroscopy (S-FTIRM). The model, based on lentiviral-mediated delivery of a fragment of the HD gene, expresses a mutant htt fragment in one brain hemisphere and a wild-type htt fragment in the control hemisphere. S-FTIRM allowed for high spatial resolution and distinction between spectral features occurring in gray and white matter. We measured a higher content of {beta}-sheet protein in the striatal gray matter exposed to mutant htt as early as 4 weeks following the initiation of mutant htt exposure. In contrast, white matter tracts did not exhibit any changes in protein structure but surprisingly showed reduced content of unsaturated lipids and a significant increase in spectral features associated with phosphorylation. The former is reminiscent of changes consistent with a myelination deficiency, while the latter is characteristic of early pro-apoptotic events. These findings point to the utility of the label-free FTIRM method to follow mutant htt's {beta}-sheet-rich transformation in striatal neurons ex vivo, provide further evidence for mutant htt amyloidogenesis in vivo, and demonstrate novel chemical features indicative of white matter changes in HD. Parallel studies in cultured neurons expressing the same htt fragments showed similar changes.},
doi = {10.1021/ac201102p},
journal = {Analytical Chemistry},
issn = {0003-2700},
number = 20,
volume = 83,
place = {United States},
year = {2011},
month = {9}
}